Chikungunya virus (CHIKV) is an alphavirus classified as a category C priority pathogen that causes fever, rash, and arthralgia in humans. In the past decade, CHIKV outbreaks have spread beyond the endemic regions of Africa and Asia, first to the islands in the Indian Ocean, and most recently to the Americas. The World Health Organization has reported that as of October 2014, over 776,000 suspected cases of Chikungunya have been recorded in the Caribbean islands, Latin American countries and some South American countries. Due to this geographic expansion of its range and the increase in the number of human cases, CHIKV is considered to be a re-emerging pathogen; a contributing factor to this re-emergence is the virus adapting to transmission by Aedes albopictus mosquitoes. Currently, there are no licensed vaccines or therapeutics to protect against infection with CHIKV. As with many viral infections, supportive care is the only available treatment. Given the severe morbidity caused by CHIKV, its swift emergence, and the lack of any targeted interventions, a preventative vaccine would provide an effective means to reduce the burden caused by this disease. This application is directed at the development of a CHIKV recombinant subunit vaccine. There are several candidate vaccines under development using a variety of platform technologies including inactivated viruses, live-attenuated viruses, chimeric live-attenuated viruses, virus- like-particles and subunits. As with all vaccines, and in particula for priority pathogens such as CHIKV which requires BSL-3 handling, a combination of safety and economics in manufacturing are of paramount importance. The proposed recombinant subunit approach provides a means to deliver a safe and stable manufacturing platform and allow for easy adjustment of dosing in order to elicit a robust immune response providing strong protection against CHIKV infection. To accomplish this goal, recombinant subunit proteins focused on specific domains with relevant epitopes from the CHIKV envelope glycoproteins will be evaluated. The Specific Aims of this project are: 1) produce recombinant CHIKV E2 subunit proteins 2) demonstrate immunogenicity of candidate vaccines in mice; and 3) demonstrate protective efficacy of candidate vaccines in mice. To achieve these goals, the recombinant E subunit proteins will be produced in an established stable insect expression system for which multiple IND applications have now been filed. A candidate vaccine will be selected on the basis of a composition that maintains native-like protein structure, and which elicits a relevant and robust immune response that is capable of preventing disease following CHIKV challenge. A collaboration between Hawaii Biotech and Baylor College of Medicine has been established to develop and evaluate a successful a CHIKV vaccine. The development of CHIKV recombinant subunit vaccine would be of great value in slowing the spread of this re-emerging Category C virus and preventing the severe morbidity caused by CHIKV infection.